Bisphosphonic acid derivatives, their production and use

ABSTRACT

Novel compounds of the formula I ##STR1## in which R 1  -R 11  can be the same or different and stand for hydrogen, a straight or branced aliphatic or alicyclic C 1  -C 10  hydrocarbon radical, an aryl or an aryl-C 1  -C 4  -alkyl radical; n is zero or one, and m is zero, one or two; or R 2  and R 4  when taken together form a saturated aliphatic 5-, 6- or 7-membered ring which may be substituted with one or more C 1  -C 4  alkyl radicals; and pharmaceutically acceptable salts and easily hydroyzable esters thereof, methods for producing said new compounds, pharmaceutical compositions containing the new compounds, dosage units of the compositions, and methods of treating patients using said compositions and dosage units. 
     The present compounds are valuable in the human and veterinary practice by reducing bone resorption and surprisingly also stimulating bone alkaline phosphatase. A substantial increase in bone mass is actually observed during treatment with the present compounds.

The present invention relates to hitherto unknown compounds useful inthe human and veterinary therapy, to pharmaceutically acceptable saltsand easily hydrolyzable esters thereof, to methods for producing saidnew compounds, to pharmaceutical compositions containing the newcompounds, to dosage units of the compositions, and to methods oftreating patients using said compositions and dosage units.

The present compounds have the formula I ##STR2## in which R₁ -R₁₁ canbe the same or different and stand for hydrogen, a straight or branchedaliphatic or alicyclic C₁ -C₁₀ hydrocarbon radical, an aryl or anaryl-C₁ -C₄ -alkyl radical; n is zero or one, and m is zero, one or two.

In addition R₂ and R₄ when taken together can form a saturated aliphatic5-, 6- or 7-membered ring which may be substituted with one or more C₁-C₄ -alkyl radicals.

In particular, R₁ -R₁₁ stand for hydrogen, C₁ -C₅ -alkyl, or phenyl.

The invention comprises all possible stereoisomeric forms of compoundsof formula I as well as mixtures thereof.

As stated above, the invention also relates to salts of the compounds offormula I which are acids and thus form salts with bases. As examples ofsalts formed with pharmaceutically acceptable, non-toxic bases, mentionmay be made of alkali metal salts and alkaline earth metal salts, suchas lithium, sodium, potassium, magnesium, calcium salts, as well assalts with ammonia and suitable non-toxic amines, such as loweralkylamines, e.g. triethylamine, lower alkanolamines, e.g.diethanolamine or triethanolamine, procaine, cycloalkylamines, e.g.dicyclohexylamine, benzylamines, e.g. N-methylbenzylamine,N-ethylbenzylamine, N-benzyl-β-phenethylamine,N,N'-dibenzylethylenediamine or dibenzylamine, and heterocyclic amines,e.g. morpholine, N-ethylpiperidine and the like.

The esters of the present compounds are in vivo easily hydrolyzable.Examples of such ester forming residues are alkanoyloxymethyl of threeto six carbon atoms, 1-(alkanoyloxy)ethyl of four to severn carbonatoms, 1-methyl-1-(alkanoyloxy)ethyl of five to eight carbon atoms,alkoxycarbonyloxymethyl of three to six carbon atoms,1-(alkoxycarbonyloxy)ethyl of four to seven carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl of five to eight carbon atoms,3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl,(2-oxo-1,3-dioxolen-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl as well as dialkylaminoalkyl,acetonyl, and methoxymethyl.

The normal bones are living tissues undergoing constant resorption andredeposition of calcium, with the net effect of maintenance of aconstant mineral balance. The dual process is commonly called "boneturnover". In normal growing bones, the mineral deposition exceeds themineral resorption, whereas in certain pathological conditions, boneresorption exceeds bone deposition resulting in e.g. hypercalcemia, forinstance due to malignancy or primary hyperparathyroidism, or inosteoporosis. In other pathological conditions the calcium depositionmay take place in undesirable amounts and areas leading to e.g.osteoarthritis, rheumatoid arthritis, kidney or bladder stones,atherosclerosis, and Paget's disease which is a combination of anabnormal high bone resorption followed by an abnormal calciumdeposition.

Most of the currently available therapeutic agents for the treatment ofosteoporosis, e.g. estrogens and calcitonin, act by reducing boneresorption in the osteoporotic patient. Since bone fracture is a severeproblem in osteoporosis, the ideal therapeutic agent should be able toincrease bone mass to a level which exceeds the fracture threshold.

Experiments in rats have shown that the compounds of the presentinvention like known bisphosphonates (e.g.1-hydroxyethylidene-1,1-bisphosphonic acid (etidronate) and3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (APD)) reduce boneresorption as shown by their inhibition of the urinary excretion ofhydroxyproline, but in contrast to these known compounds which alsoinhibit bone alkaline phosphatase, the new compounds of this inventionsurprisingly stimulate bone alkaline phosphatase, indicating astimulation of the bone forming cells--the osteoblasts--and asubstantial increase in bone mass is actually observed during treatmentwith the present compounds.

The compounds of the present invention (n=0) may be prepared from acompound of formula II ##STR3## where R₁ -R₁₁ and m have the meaningsmentioned above. The compounds of formula II are either known or may beprepared in analogy with the known compounds. They are transformed intoacid amide chlorides of formula III by treatment with e.g. phosgene oroxalyl chloride ##STR4## (R₁ -R₁₁ and m as defined above).

Reaction of compounds of formula III with trialkylphosphites leads totetraalkyl esters of formula IV ##STR5## where R₁ -R₁₁ and m have themeanings defined above and R₁₂ is a C₁ -C₄ -alkyl radical, preferablymethyl or ethyl, or a benzyl or a substituted benzyl radical.

Cleavage of the esters of formula IV by hydrolysis, e.g. with boilinghydrochloric acid, or by hydrogenolysis, leads to the compounds offormula I (n=0).

The esters may also be cleaved by an alternative method described inJour. f. prakt. Chemie 320, 344 (1978). Treatment withbromotrimethylsilane at room temperature or moderately elevatedtemperature leads to a tetra-trimethylsilyl ester which is easilycleaved with water or alcohol to yield the free acid or formula I.

Alternatively, compounds of formula I (n=0) may be prepared by reactingcompounds of formula II with phosphorous acid and phosphorus trichloridefollowed by hydrolysis of the reaction mixture.

Compounds of formula I in which n=1 may be prepared by oxidation ofcompounds of formula I or IV (n=0) with the well known reagents for thepreparation of sulfoxides from sulfides, e.g. 3-chloroperbenzoic acid orhydrogen peroxide, optionally followed by ester cleavage.

Easily hydrolyzable esters of the compounds of formula I may be preparedby reacting a salt, e.g. a silver salt or a quaternary ammonium salt, ofa compound of formula I with a reactive halide corresponding to thedesired ester.

Tetra-esters may be cleaved by reaction with an iodide, e.g. sodiumiodide, to form di-esters of the compounds of formula I.

The present compounds are as mentioned above intended for use inpharmaceutical compositions which are useful in the treatment ofosteoporosis, rheumatoid arthritis and other arthritic disorders,atherosclerosis, hypercalcemia due to malignancies or primaryhyperparathyroidism, Paget's disease, and other conditions with anabnormal calcium balance.

The present compounds may also be used in toothpastes in order toprevent calcium deposition in the form of dental calculus or in order toprotect against calcium resorption due to acid dissolution.

The amount required of a compound of formula I (hereinafter referred toas the active ingredient) for therapeutic effect will, of course, varyboth with the particular compound, the route of administration and themammal under treatment. A suitable dose of a compound of formula I for amammal suffering from e.g. a hypercalcemic condition as definedhereinbefore is 0.001 to 25 mg per kilogram bodyweight, the mostpreferred dosage being 0.002 to 10 mg/kg of mammal bodyweight, forexample 0.005 to 5 mg/kg; administered once or more times daily.

In the case of the profylactic treatment of e.g. postmemopausalosteoporosis, a suitable dose of a compound of formula (I) is 0.001 to10 mg per kilogram bodyweight, the most preferred dosage being 0.002 to5 mg/kg of mammal bodyweight.

While it is possible for an active ingredient to be administered aloneas the pure compound, it is preferable to present it as a pharmaceuticalformulation. Conveniently, the active ingredient comprises from 0.1% to99.9% by weight of the formulation. Conveniently, dosage units of aformulation contain between 0.1 mg and 1 g of the active ingredient. Fortopical administration, the active ingredient preferably comprises from1% to 2% by weight of the formulation but the active ingredient maycomprise as much as 10% w/w.

By the term "dosage unit" is meant a unitary, i.e. a single dose whichis capable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically stable unit dosecomprising either the active material as such or a mixture of it withsolid or liquid pharmaceutical diluents or carriers.

The formulations, both for veterinary and for human medical use, of thepresent invention comprise an active ingredient in association with apharmaceutically acceptable carrier and optionally other therapeuticingredient(s). The carrier(s) must be "acceptable" in the sense of beingcompatible with the other ingredients of the formulations and notdeleterious to the recipient thereof.

The formulations include those in a form suitable for oral, rectal,parenteral (including subcutaneous, intramuscular and intravenous), ortopical administration.

The formulations may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationsmay be in the form of discrete units as capsules, sachets, tablets orlozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or non-aqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be in the form of bolus, electuary or paste.

Formulations for rectal administration may be in the form of asuppository incorporating the active ingredient and a carrier such ascocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active ingredient which ispreferably isotonic with the blood of the recipient.

Formulations suitable for topical administration include liquid orsemi-liquid preparations such as liniments, lotions, applications;oil-in-water or water-in-oil emulsions such as creams, ointments orpastes, including tooth-pastes; or solutions or suspensions such asdrops.

In addition to the aforementioned ingredients, the formulations of thisinvention may include one or more additional ingredients such asdiluents, buffers, flavouring agents, binders, surface active agents,thickeners, lubricants, preservatives, e.g. methylhydroxybenzoate(including anti-oxidants), emulsifying agents and the like.

The compositions may further contain other therapeutically activecompounds usually applied in the treatment of the above mentionedpathological conditions, for instance vitamin D₂ and D₃ and hydroxylatedderivatives, e.g. 1α-hydroxy-vitamin D₃, 1α-hydroxy-vitamin D₂,1α,25-dihydroxy-vitamin D₃, 1α,25-dihydroxy-vitamin D₂, calcitonin(human, porcine or salmon), mitramycin, sodium fluoride, estrogens, andnon-steroid antiinflammatory drugs, e.g. acetylsalicyclic acid,indomethacin, naprosyn, and timegadine.

According to the invention, the present compounds are administered to apatient suffering from one of the above mentioned pathologicalconditions in a daily dose (for adults) from 0.07 mg to 1750 mg,preferably from 0.15-1000 mg, and in the veterinary practicecorrespondingly in daily doses from 0.001 to 25 mg/kg bodyweight.

The invention will now be further described in the followingnon-limiting Preparations and Examples:

PREPARATION 1 5,5-Dimethyl-3-thiomorpholinone

2,2-Dimethylaziridine (35.5 g) was added dropwise with stirring at 100°C. to methyl mercaptoacetate (53 g) during 1.5 hours. After a further 2hours at 100° C., the mixture was cooled and crystallized from ethylacetate. Melting point: 151-152° C.

PREPARATION 2 3,3-Dimethyl-thiomorpholine

5,5-Dimethyl-3-thiomorpholinone (50 g) was added in portions to astirred suspension of lithium aluminium hydride (25 g) intetrahydrofuran (1000 ml). After 20 hours reflux, unreacted lithiumaluminium hydride was destroyed by the addition of sodium sulfatedecahydrate. The mixture was filtered, and the filtrate was evaporatedin vacuo. Distillation in vacuo gave the title compound with boilingpoint 71°-72° C./15 mmHg.

PREPARATION 3 2,5,5-Trimethyl-3-thiomorpholinone

This compound was obtained from 2,2-dimethylaziridine andmethyl-2-mercaptopropionate as described in Preparation 1.

Melting point: 137°-138° C.

PREPARATION 4 2,5,5-Trimethyl-thiomorpholine

This compound was prepared as described in Preparation 2 by substituting2,5,5-trimethyl-3-thiomorpholinone for 5,5-dimethyl-3-thiomorpholinone.Boiling point: 76°-77° C./15 mmHg.

PREPARATION 5 2-(1-Butyl)-3-thiomorpholinone

Potassium hydroxide (56 g) was added to a suspension of cysteamine,hydrochloride (56.6 g) in absolute ethanol (300 ml) followed by dropwiseaddition of ethyl 2-bromohexanoate (111.5 g). When the exothermicreaction ceased, the mixture was refluxed for 3 hours and filtered.Concentration of the filtrate in vacuo gave the title compound as aviscous oil which was used in the next step without purification.

PREPARATION 6 2-(1-Butyl)-thiomorpholine, hydrochloride

This compound was prepared as described in Preparation 2 by substituting2-(1-butyl)-3-thiomorpholinone for 5,5-dimethyl-3-thiomorpholinone.

A solution of the crude 2-(1-butyl)-thiomorpholine in ether was treatedwith an excess of hydrogen chloride in ether to yield a crystallinehydrochloride with melting point 104° C.

Microanalysis: Calculated: C: 49.08, H: 9.27, N: 7.16, S: 16.38, Cl:18.11. Found: C: 49.12, H: 9.34, N: 7.09, S: 16.19, Cl: 18.00.

PREPARATION 7 N-Formyl-thiomorpholine

Chloral (10 ml) was added dropwise to a solution of thiomorpholine (10g) in tetrachloromethane (50 ml), and the resulting mixture was refluxedfor 1 hour. Distillation in vacuo gave N-formyl-thiomorpholine withboiling point 140° C./15 mmHg. When kept at room temperature, the pureproduct formed low melting crystals.

PREPARATION 8

By following the procedure described in Preparation 7 and substitutingthe appropriately substituted thiomorpholine for thiomorpholine itself,the following compounds were prepared:

N-Formyl-2-methyl-thiomorpholine: B.p.: 141°-142° C./15 mmHg

N-Formyl-3-methyl-thiomorpholine: B.p.: 146°-147° C./15 mmHg

N-Formyl-3,3-dimethyl-thiomorpholine: B.p.: 155°-156° C./15 mmHg

N-Formyl-2,5,5-trimethyl-thiomorpholine: B.p.: 154°-155° C./15 mmHg

N-Formyl-2-ethyl-thiomorpholine: B.p. 75° C./1.5 mmHg

N-Formyl-2,2-dimethyl-thiomorpholine: B.p.: 75°-76° C./1 mmHg

N-Formyl-3-ethyl-thiomorpholine: B.p.: 145°-146° C./15 mmHg

N-Formyl-2-(1-butyl)-thiomorpholine: B.p.: 160°-162° C./15 mmHg

N-Formyl-2-phenyl-thiomorpholine: B.p.: 148°-150° C./1 mmHg

PREPARATION 9 N-Formyl-2,6-dimethyl-thiomorpholine

Piperidine (10 ml) and 10 ml of a 40% solution ofbenzyltrimethylammoniumhydroxide in methanol were added to a solution ofN-formyl-diallylamine (55 g) in methanol (200 ml). Hydrogen sulfide (50g) was introduced into the resulting solution, and unreacted hydrogensulfide was kept at reflux for 7 hours by means of "cold finger". Themixture was left at room temperature for 48 hours, flushed withnitrogen, diluted with ether, and washed with water. The organic phasewas dried, and the solvent evaporated in vacuo. Distillation of theresidue gave the title compound with boiling point 145° C./15 mmHg.

PREPARATION 10 N-Formyl-3-ethyl-2-methyl-thiomorpholine

Cysteamine, hydrochloride (68.2 g, 0.6 mole) was added to an ice-coldstirred solution of sodium (27.6 g, 1.2 mole) in ethanol (1000 ml).α-Bromo-diethyl ketone (99 g, 0.6 mole) was then added slowly in anitrogen atmosphere while the temperature was kept below 25° C.

After stirring for 2 hours, the mixture was filtered, and the filtrateevaporated in vacuo to leave an oil which was taken up in water (300 ml)and extracted with ether (2×500 ml). The organic phase was separated,dried and evaporated to give an oil which was distilled in vacuo. Thedistillate (b.p. 70° C./1 mmHg) wsa heated to 140° C. with stirring, andformic acid (100 ml) was added at such a rate that the temperature waskept at 135°-140° C. without external heating. After standing overnightat room temperature, the stirred mixture was slowly treated with 40%potassium hydroxide (200 ml) and extracted with ether (2×500 ml). Theorganic phase was dried and concentrated to about 500 ml. Chloral (80ml) was added, and the mixture was refluxed for 1 hour, cooled andevaporated to leave an oil which was distilled in vacuo to give thetitle compound with b.p.: 102°-104° C./1 mmHg.

PREPARATION 11

By following the procedure described in Preparation 10 and substitutingthe appropriate α-bromo ketones for α-bromo-diethyl ketone, thefollowing compounds were prepared:

N-Formyl-2,3-dimethyl-thiomorpholine: B.p.: 88°-90° C./1 mmHg

N-Formyl-2-isopropyl-3-methyl-thiomorpholine: B.p. 125°-126° C./1 mmHg

N-Formyl-2-isobutyl-3-methyl-thiomorpholine: B.p. 115°-116° C./1 mmHg

N-Formyl-perhydro-1,4-benzothiazine: M.p.: 70°-71° C. B.p.: 128°-130°C./1 mmHg.

N-Formyl-7-methyl-perhydro-1,4-benzothiazine: M.p.: 135°-136° C.

N-Formyl-3-isobutyl-thiomorpholine: B.p.: 110°-114° C./1 mmHg

PREPARATION 12

By using the appropriate starting materials and following the proceduresdescribed in Preparations 1, 2 and 7, the following compounds wereprepared.

N-Formyl-2-isobutyl-thiomorpholine: B.p.: 150°-155° C./15 mmHg

N-Formyl-2,5-dimethyl-thiomorpholine: B.p.: 142°-143° C./15 mmHg

PREPARATION 13

By repeating the procedure of Preparation 10 and replacingα-bromo-diethyl ketone by the appropriate α-bromo ketones, the followingcompounds were prepared.

N-Formyl-3-(n-propyl)-thiomorpholine

N-Formyl-3-isopropyl-thiomorpholine B.p.: 95°-96° C./1 mmHg

N-Formyl-3-phenyl-thiomorpholine

N-Formyl-2-ethyl-3-methyl-thiomorpholine

N-Formyl-3-(n-butyl)-thiomorpholine

N-Formyl-2-ethyl-3-propyl-thiomorpholine B.p.: 122°-123° C./1 mmHg

N-Formyl-2-isopropyl-3-isobutyl-thiomorpholine B.p.: 122°-123° C./1 mmHg

N-Formyl-2,2-dimethyl-3-isopropyl-thiomorpholine B.p.: 116°-117° C./1mmHg

N-Formyl-3-cyclopropyl-thiomorpholine B.p.: 109°-110° C./1 mmHg

N-Formyl-3-nonyl-thiomorpholine B.p.: 147°-148° C./1 mmHg

N-Formyl-3-tert-butyl-thiomorpholine B.p.: 113°-114° C./1 mmHg

N-Formyl-2,2-dimethyl-3-phenyl-thiomorpholine

N-Formyl-3-methyl-2-phenyl-thiomorpholine

N-Formyl-3-isopentyl-thiomorpholine

N-Formyl-3-cyclohexyl-thiomorpholine

N-Formyl-2-phenyl-3-benzyl-thiomorpholine

N-Formyl-2-pentyl-3-hexyl-thiomorpholine

PREPARATION 14 3-tert-Butyl-thiomorpholine

This compound was prepared as described in Preparation 10 by usingbromomethyl tert-butyl ketone instead of α-bromo-diethyl ketone and byomitting the treatment with chloral. The title compound was distilled invacuo, b.p.: 73°-74° C./1 mmHg.

PREPARATION 15 (+)-3-tert-Butyl-thiomorpholine

3-tert-Butyl-thiomorpholine (159 g, racemic form described inPreparation 14) was added to a hot solution of (+)-tartaric acid (150 g)in water (100 ml). The mixture was left overnight and filtered. Thecrystalline salt which showed [α]_(D) ²⁰ =+20° (c=1, H₂ O) wasrecrystallized repeatedly from water until [α]_(D) ²⁰ =+32° (c=1, H₂ O).The free base was liberated with an excess of 30% potassium hydroxideand taken up in ether. The solution was dried and evaporated to leavethe title compound as an oil with [α]_(D) ²⁰ =+36.1° (c=1, EtOH).

PREPARATION 16 (-)-3-tert-Butyl-thiomorpholine

3-tert-Butyl-thiomorpholine--liberated from the combined filtratesobtained in Preparation 15 during the preparation of the tartrate--wastreated with (-) tartaric acid in water. The resulting tartrate wasrecrystallized until [α]_(D) ²⁰ =-31.4° (c=1, H₂ O). The free baseshowed [α]_(D) ²⁰ =-36.0° (c=1, EtOH).

PREPARATION 17

The compounds prepared in Preparation 15 and 16 were formylated withchloral as described in Preparation 7 to yield

(+)-N-formyl-3-tert-butylthiomorpholine [α]_(D) ²⁰ =+108° (c=1, EtOH)and

(-)-N-formyl-3-tert-butylthiomorpholine [α]_(D) ²⁰ =-107° (c=1, EtOH).

PREPARATION 18

By following the procedures described in Examples 15, 16 and 17 othersubstituted thiomorpholines may be resolved into the enantiomers andsubsequently formylated to form e.g.

(+)-N-formyl-3-isobutylthiomorpholine

(-)-N-formyl-3-isobutylthiomorpholine

PREPARATION 19 N-Formyl-tetrahydro-1,4-thiazepin-3-one

To a solution of sodium (23 g) in absolute ethanol (1 l) was added ethylthioglycolate (60.1 g) and 3-bromopropylamine, hydrobromide (109.5 g).After reflux for 12 hours, the mixture was cooled and filtered. Thefiltrate was evaporated in vacuo, and the residue was crystallized fromethanol to yield tetrahydro-1,4-thiazepin-3-one with m.p. 145°-148° C.60 g of this product was added in portions to a stirred suspension oflithium aluminium hydride (25 g) in tetrahydrofuran (2.5 l). The mixturewas kept at 45°-50° C. for 2 hours followed by reflux for a further 2hours. After cooling a mixture of water (62 ml) and tetrahydrofuran (250ml) was added dropwise with stirring. Filtration and evaporation of thefiltrate gave a residue which was dissolved in ether (250 ml), driedover magnesium sulfate, filtered and treated dropwise with chloral (40ml). After reflux for 1 hour the solvent was evaporated, and the residuedistilled in vacuo to yield the title compound with b.p. 158°-159° C./18mmHg.

PREPARATION 20 N-Formyl-2-methyl-tetrahydro-1,4-thiazepin-3-one

This compound was prepared by following the procedure of Preparation 19,but substituting ethyl 2-mercaptopropionate for ethyl thioglycolate.2-Methyl-tetrahydro-1,4-thiazepin-3-one with m.p. 192°-193° C. wasisolated as an intermediate. The title compound was colourless oil withb.p. 104°-105° C./1 mmHg.

EXAMPLE 1 (4-Thiomorpholinylmethylene)-bisphosphonic acid

Oxalyl chloride (16.6 ml) was added dropwise at 0° C. to a stirredsolution of N-formyl-thiomorpholine (26.2 g) in methylene chloride (200ml). The mixture was stirred at room temperature until the gas evolutionceased (about 5 hours later). Triethyl phosphite (66 ml) was then addedduring 1.5 hours at room temperature. Unreacted triethyl phosphite wasremoved in vacuo, and the residue was refluxed with 20% hydrochloricacid (150 ml) for 3 hours. The mixture was evaporated to dryness invacuo, and the residue was stirred with acetone. The crystalline productwas filtered and recrystallized from water. M.p.: >250° C. (dec.).

Microanalysis: Calculate: C: 21.67, H: 4.73, N: 5.05, S: 11.57. Found:C: 21.56, H: 4.77, N: 4.95, S: 11.35.

NMR (NaOD, TMS=0.0 ppm as reference): δ=2.8-3.1 (m, 4H); 3.21 (t, J=18Hz, 1H) and 3.7-4.0 (m, 4H) ppm.

EXAMPLE 2

By following the procedure described in Example 1 and substituting theappropriate N-formyl-derivatives described in Preparations 8, 9, 10, 11and 12 for N-formyl-thiomorpholine, the following compounds wereprepared:

(2-Methyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: >250° C.(dec). NMR (NaOD, HDO=4.66 ppm as reference): δ=1.20 (d, J=6.8 Hz, 3H)and 2.7-3.8 (m, 8H) ppm.

(2-(1-Butyl)-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:226°-227° C. NMR (NaOD, HDO=4.66 ppm as reference): δ=0.78 (t, 3H); 1.28(bs, 6H) and 2.4-3.6 (m, 8H) ppm.

(2-Ethyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: 237°-238°C. NMR (NaOD, HDO=4.66 ppm as reference): δ=0.85 (m, 3H); 1.40 (m, 2H)and 2.4-3.4 (m, 8H) ppm.

(3,3-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid: NMR (NaOD,HDO=4.66 ppm as reference): δ=1.52 (bs, 6H); 2.91 (bs, 2H) and 2.8-4.0(m, 5H) ppm.

(2,5,5-Trimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:200° C. (dec.). NMR (NaOD, HDO=4.66 ppm as reference): δ=1.20 (d, J=7Hz, 3H); 1.48 (s, 3H); 1.58 (s, 3H) and 2.6-4.0 (m, 6H) ppm.

(2-Phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: 250° C.(dec.). NMR (NaOD, HDO=4.66 ppm as reference): δ=2.4-3.6 (m, 7H); 4.0(m, 1H) and 7.25 (m, 5H) ppm.

(2,2-Dimethyl-4-thiomorpholinylmethylene)bisphosphonic acid: M.p.:246°-247° C. NMR (NaOD, HDO=4.66 ppm as reference): δ=1.37 (s, 6H); 3.00(bt, 2H); 3.41 (t, J=18.5 Hz, 1H); 3.61 (bs, 2H) and 3.75 (bt, 2H) ppm.

(3-Methyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:221°-222° C. NMR (NaOD, HDO=4.66 ppm as reference): δ=1.46 (d, J=6.5 Hz,3H); 2.4-3.2 (m, 4H) and 3.5-4.3 (m, 4H) ppm.

(3-Ethyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: 226°-227°C. NMR (NaOD, TMS=0.0 ppm as reference): δ=1.01 (t, 3H); 2.00 (m, 2H);2.9-3.2 (m, 4H); 3.5 (t, 1H) and 3.7-4.3 (m, 3H) ppm.

(2,6-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: 245°C. (dec.). NMR (NaOD, TMS=0.0 ppm as reference): δ=1.4 (m, 6H) and3.1-4.0 (m, 7H) ppm.

(2,5-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid,monohydrate: M.p.: 219°-220° C. NMR (NaOD, TMS=0.0 ppm as reference):δ=1.4-1.8 (m, 6H), 3.2 (d, 2H) and 3-4.5 (m, 5H) ppm,

(2,3-Dimethyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:200°-202° C. NMR (D₂ O, HDO=4.66 ppm as reference): δ=1.18 (m, 3H), 1.43(m, 3H) and 2.5-4.3 (m, 7H) ppm.

(2-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: 238°C. (dec.). NMR (NaOD, HDO=4.66 ppm as reference): δ=0.83 (d, 6H); 1.35(t, 2H); 1.7 (m, 1H) and 2.75-4.0 (m, 8H) ppm.

(2-Isobutyl-3-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid,disodium salt: NMR (D₂ O, TMS=0.0 ppm as reference): δ=0.93 (m, 6H);1.1-2 (m, 6H) and 2.9-4.3 (m, 7H) ppm.

(3-Ethyl-2-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid: NMR(NaOD, HDO=4.66 ppm as reference): δ=0.83 (t, 3H), 1.17 (m, 3H); 1.8-2.1(m, 2H) and 2.5-4.25 (m, 7H) ppm.

(2-Isopropyl-3-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid:M.p.: 214°-216° C. NMR (NaOD, HDO=4.66 ppm as reference): δ=0.95 (m,6H); 1.47 (d, 3H); 1.55 (m, 1H); 3.46 (t, J=16 Hz, 1H) and 2.6-4.7 (m,6H) ppm.

[(7-Methyl-perhydro-1,4-benzothiazin-4-yl)-methylene]-bisphosphonicacid: M.p.: 256°-257° C. NMR (NaOD, HDO=4.66 ppm as reference): δ=0.80(d, 3H), 0.9-2.0 (m, 6H), 2.2-2.5 (m, 1H) and 2.6-4.3 (m, 7H) ppm.

[(Perhydro-1,4-benzothiazin-4-yl)-methylene]-bisphosphonic acid: M.p.:257°-258° C. NMR (NaOD, HDO=4.66 ppm as reference): δ=0.9-2.0 (m, 7H);2.2-3.8 (m, 7H) and 4.15 (bd, 1H) ppm.

(3-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:237°-238° C. (dec.). NMR (NaOD, TMS=0.0 ppm as reference): δ0.97 (bm,6H); 1.4-2.0 (m, 3H); 2.5-3.2 (m, 4H) and 3.3-4.0 (m, 4H) ppm.

EXAMPLE 3 [1-(4-Thiomorpholinyl)-ethylidene]-bisphosphonic acid,bis-benzylamine salt

A mixture of N-acetyl-thiomorpholine (14.5 g) and phosphorous acid (24.6g) was heated at 100° C. for 3 hours. Phosphorus trichloride (41.1 g)was added dropwise with stirring and after reflux for 3 hours, water (80ml) was added slowly, and the mixture was kept at 100° C. for 3 hours.Filtration and evaporation of the filtrate gave an oil which was takenup in ethanol. The title compound was precipitated by the addition ofether. The crude product was transformed into a bis-benzylamine saltwith m.p.: 223°-224° C. NMR (D₂ O, HDO=4.66 ppm as reference): δ=1.51(t, J=13 Hz, 3H); 2.95 (t, 4H); 3.85 (m, 4H); 4.07 (s, 4H) and 7.36 (s,10H) ppm.

EXAMPLE 4 Tetrabenzyl (4-thiomorpholinylmethylene)-bisphosphonatesulfoxide

Oxalyl chloride (0.85 ml) was added dropwise at -10° C. to a stirredsolution of N-formyl-thiomorpholine (1.31 g) in tetrahydrofuran (10 ml),and the mixture was stirred at -10° C. for 1 hour.

A solution of sodium dibenzylphosphite in tetrahydrofuran (20 ml)(prepared from dibenzylphosphite (8.4 g) and 55% NaH (1.08 g)) wasadded, and after stirring for 1 hour the solvent was evaporated and theremaining oil distributed between water and methylene chloride. Theorganic phase was dried and evaporated to leave an oil which waspurified by flash chromatography on silica gel (ether:acetone 90:10 aseluent) to yield tetrabenzyl (4-thiomorpholinylmethylene)-bisphosphonate(1.27 g) which was taken up in alcoholfree chloroform (15 ml). Thissolution was cooled in ice and treated dropwise with a solution of 90%3-chloroperbenzoic acid (0.38 g) in alcoholfree chloroform (5 ml). Theice bath was removed, and after stirring for a further 90 minutes thesolvent was removed in vacuo, and the residue was purified bychromatography on silica gel to give the title compound as a colourlessoil. NMR (CDCl₃, TMS=0.0 ppm as reference): δ=2.62 (bt, 4H); 3.0 (bm,2H); 3.36 (t, J=25 Hz, 1H); 3.60 (bm, 2H); 5.04 (m, 8H) and 7.30 (s,20H) ppm.

EXAMPLE 5 (4-Thiomorpholinylmethylene)-bisphosphonic acid sulfoxide

To a solution of tetrabenzyl (4-thiomorpholinylmethylene)-bisphosphonatesulfoxide (1 g) in ethyl acetate (15 ml) were added water (15 ml) and10% palladium on carbon (1 g). The resulting mixture was shakenvigorously in a hydrogen atmosphere until the consumption of hydrogenceased. The catalyst was removed by filtration, and the aqueous phasewas separated and freeze-dried to yield the title compound as anamorphous powder. NMR (NaOD, HDO=4.66 ppm as reference): δ=2.75 (t,J=22.6 Hz, 1H): 2.7-3.25 (m, 6H) and 3.3-3.7 (m, 2H) ppm.

EXAMPLE 6

The procedure of Example 1 is repeated, except thatN-formyl-thiomorpholine is replaced by the appropriate N-formylderivatives described in Preparation 13. This affords:

[3-(n-Propyl)-4-thiomorpholinylmethylene]-bisphosphonic acid

(3-Isopropyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:240°-241° C.

(3-Phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:257°-258° C. (d).

(2-Ethyl-3-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid

[3-(n-Butyl)-4-thiomorpholinylmethylene]-bisphosphonic acid

EXAMPLE 7 (3-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid

A mixture of N-formyl-3-isobutyl-thiomorpholine (18.7 g) and phosphorousacid (16.4 g) was heated at 100° C. for 2 hours. Phosphorus trichloride(30 ml) was added dropwise with stirring, and after reflux for 3 hourswater (180 ml) was added slowly. The mixture was refluxed for 1 hour andfiltered. Evaporation of the filtrate gave a residue which wastriturated with ethanol to yield a crystalline compound which wasisolated by filtration. M.p.: 237°-238° C. (dec.).

EXAMPLE 8

The procedure of Example 7 was repeated, except thatN-formyl-3-isobutyl-thiomorpholine was replaced by the appropriateN-formyl-derivative described in Preparation 13, 17 and 18. In this waythe following compounds were prepared:

(3-Phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: 257° C.(dec.).

(2-Ethyl-3-propyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:213°-215° C.

(3-Isopropyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:240°-241° C.

(2-Isopropyl-3-isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid:M.p.: 225° C.

(2,2-Dimethyl-3-isopropyl-4-thiomorpholinylmethylene)-bisphosphonicacid: M.p.: 202°-205° C.

(2,2-Dimethyl-3-phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid:M.p.: 242° C.

(3-Methyl-2-phenyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:251° C. (dec.)

(3-Cyclopropyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:221° C. (dec.)

(3-Nonyl-4-thiomorpholinylmethylene)-bisphosphonic acid M.p.: 197°-200°C.

(3-Tert.butyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.: 217°C. (dec.).

(+)-(3-Tert.butyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:216°-217° C. (dec.). [α]_(D) ²⁰ =+33.4° (c=1, 1N NaOH).

(-)-(3-Tert.butyl-4-thiomorpholinylmethylene)-bisphosphonic acid: M.p.:216°-217° C. (dec.). [α]_(D) ²⁰ =-33.8° (c=1, 1N NaOH).

(3-Isopentyl-4-thiomorpholinylmethylene)-bisphosphonic acid

(3-Cyclohexyl-4-thiomorpholinylmethylene)-bisphosphonic acid

(+)-(3-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid: [α]_(D)²⁰ =+54° (c=1, 1N NaOH)

(-)-(3-Isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid: [α]_(D)²⁰ =-54.3° (c=1, 1N NaOH)

(2-Phenyl-3-benzyl-4-thiomorpholinylmethylene)-bisphosphonic acid

(2-pentyl-3-hexyl-4-thiomorpholinylmethylene)-bisphosphonic acid

EXAMPLE 9 Disodium (4-thiomorpholinylmethylene)-bisphosphonatesulfoxide, monohydrate

30% Aqueous hydrogen peroxide (11.1 ml) was added with stirring to asolution of (4-thiomorpholinylmethylene)-bisphosphonic acid (27.7 g) in5M NaOH (40 ml). When the exothermic reaction had ceased the solvent wasevaporated, and the residue was treated with ethanol and filtered toyield the title compound as colourless crystals. The NMR-spectrum wasidentical with that described in Example 5.

EXAMPLE 10

By following the procedure described in Example 9 the followingsulfoxides were prepared:

Disodium ]3-(tert.butyl)-4-thiomorpholinylmethylene]-bisphosphonatesulfoxide

Disodium (3-isobutyl-4-thiomorpholinylmethylene)-bisphosphonatesulfoxide

Disodium (3-cyclopropyl-4-thiomorpholinylmethylene)-bisphosphonatesulfoxide

EXAMPLE 11

By following the procedure of Example 1, but substituting theN-formyl-derivatives of Preparation 19 and 20 forN-formyl-thiomorpholine the following compounds were prepared:

(Tetrahydro-1,4-thiazepin-4-yl-methylene)-bisphosphonic acid: M.p.:239°-240° C.

(2-Methyl-tetrahydro-1,4-thiazepin-4-yl-methylene)-bisphosphonic acid:M.p.: 241° C.

EXAMPLE 12 Tetra-pivaloyloxymethyl(4-thiomorpholinylmethylene)-bisphosphonate

A solution of (4-thiomorpholinylmethylene)-bisphosphonic acid (2.8 g) inwater (60 ml) was treated with four equivalents of aqueoustetrabutylammonium hydroxide and freeze-dried. Remaining water wasremoved azeotropically with toluene. The resulting salt was suspended intetrahydrofuran (120 ml), and iodomethyl pivalate (9.4 ml) was addedwith stirring. After stirring for 1 hour at room temperature, themixture was filtered, and the filtrate evaporated in vacuo. The residuewas taken up in ethyl acetate and washed with aqueous sodiumbicarbonate, dried and evaporated in vacuo. Chromatography on silica gel(eluent: petroleum ether--ethyl acetate 7:3) gave the pure titlecompound which crystallized on standing. M.p.: 86°-88° C. NMR (CDCl₃):δ=1.24 (s, 36H); 2.65 (m, 4H); 3.25 (m, 4H); 3.55 (t, J=26 Hz, 1H) and5.70 (m, 8H) ppm.

EXAMPLE 13 Tetra-acetoxymetyl(4-thiomorpholinylmethylene)-bisphosphonate

By following the procedure described in Example 12, but substitutingiodomethyl acetate for iodomethyl pivalate, the title compound wasobtained as a colourless oil. NMR (CDCl₃): δ=2.14 (s, 6H); 2.16 (s, 6H);2.65 (m, 4H); 3.26 (m, 4H); 3.53 (t, J=26 Hz, 1H) and 5.70 (m, 8H) ppm.

EXAMPLE 14 Di-pivaloyloxymetyl(4-thiomorpholinylmethylene)-bisphosphonate disodium salt

A solution of tetra-pivaloyloxymethyl(4-thiomorpholinylmethylene)-bisphosphonate (0.37 g) and sodium iodide(0.22 g) in acetone (5 ml) was refluxed for 90 minutes, cooled andfiltered to yield the title compound as colourless crystals.

NMR: (D₂ O): δ=1.16 (s, 18H); 2.65 (m, 4H); 3.05 (t, 1H); 3.18 (m, 4H)and 5.52 (m, 4H) ppm.

EXAMPLE 15 Di-acetoxymethyl (4-thiomorpholinylmethylene)-bisphosphonatedisodium salt

This compound was prepared from tetra-acetoxymethyl(4-thiomorpholinylmethylene)-bisphosphonate by following the procedureof Example 14. NMR (D₂ O): δ=2.09 (s, 6H); 2.65 (m, 4H): 3.10 (t, 1H);3.25 (m, 4H) and 5.50 (m, 4H) ppm.

We claim:
 1. A compound of the formula I ##STR6## in which R₁ -R₇ can bethe same or different and stand for hydrogen, a straight, branched orcyclic C₁ -C₁₀ hydrocarbon radical, phenyl or a phenyl -C₁ -C₄ -alkylradical; R₈ -R₁₁ each stand for hydrogen n is zero or one, and m iszero, one or two; and pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1, in which R₁ -R₇, being the same ordifferent, stand for hydrogen, C₁ -C₅ -alkyl or phenyl.
 3. A saltaccording to claim 1, which is a salt of a compound of formula I with apharmaceutically acceptable non-toxic base, such salt being selectedfrom the group consisting of alkali metal salts, alkaline earth metalsalts, or salts with ammonia or suitable non-toxic amines, such as loweralkylamines, lower alkanolamines, procaine, cycloalkylamines,benzylamines, and heterocyclic amines.
 4. A compound of formula Iaccording to claim 1, selected from the group consistingof(4-thiomorpholinylmethylene)-bisphosphonic acid and its salts, and(3-isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid in racemicform or in the form of the single enantiomers, and salts, and(3-tert-butyl-4-thiomorpholinylmethylene)-bisphosphonic acid in racemicform or in the form of the single enantiomers, and salts, and(2-methyl-4-thiomorpholinylmethylene)-bisphosphonic acid in racemic formor in the form of the single enantiomers, and salts.
 5. A method forproducing a compound of formula I of claim 1, in which a compound offormula II ##STR7## where R₁ -R₁₁ and m have the meanings defined inclaim 1, is transformed into an acid amide chloride which is reactedwith a trialkylphosphite to form a compound of formula IV ##STR8## whereR₁ -R₁₁ and m have the meanings defined in claim 1, and R₁₂ is a C₁ -C₄-alkyl radical or a benzyl or a substituted benzyl radical, whereafterthe compound of formula IV thus produced is hydrolyzed or hydrogenolyzedto form the desired compound of formula I (n=0), or the compound offormula IV is optionally oxidized to form a compound in which n=1,followed by a hydrolysis or hydrogenolysis as above to form the desiredcompound of formula I (n=1); the final compound of formula I beingrecovered as such or as a salt as defined in claim
 1. 6. A method forproducing a compound of formula I of claim 1, in which a compound offormula II, where R₁ -R₁₁ and m have the meanings defined in claim 1, isheated with a mixture of phosphorous acid and phosphorus trichloride orphosphorus oxychloride followed by a hydrolysis to form the desiredcompound of formula I (n=0) optionally followed by an oxidation to forma compound of formula I (n=1), the final compound of formula I beingrecovered as such or as a salt as defined in claim
 1. 7. Apharmaceutical composition, containing an effective amount of one ormore of the compounds of claim 1, together with pharmaceuticallyacceptable, non-toxic carriers and/or auxiliary agents.
 8. A method forthe treatment of a patient suffering from osteoporosis, rheumatoidarthritis or other arthritic disorder, atherosclerosis, hypercalcemiadue to malignancies or primary hyperparathyroidism, Pagets disease, orother condition with an abnormal calcium balance, in which a compositionaccording to claim 7 is administered to the patient in need oftreatment.